Down's syndrome (DS), first described more than a century ago, is still the most common genetic abnormality, occurring once per 000 live births. The syndrome is manifested by morphogenetic abnormalities, mental retardation, immunological abnormalities and at large stage the pathological manifestation of Alzheimer's disease. DS results from the presence in the cell of an extra copy of chromosome 21, or a portion of it, the 21q22 segment. It is assumed that the additional 21q22 codes for normal products, and that the abnormalities found in the syndrome are produced by an imbalance due to change in gene dosage. The risk of a child being born with trisomy 21 increases sharply with maternal age; since there is presently a trend for many couples to postpone parenthood until the fourth decade of life, the incidence of DS babies is expected to increase. Moreover, because of continuous improvement in all aspects of clinical treatment, life expectancy of DS patients has tripled over the last two decades. Thus, despite the institution of prenatal screening by amniocentesis of at-risk pregnancies, the prevalence of DS individuals in our society will not significantly decrease in the future. The long-term objective of this research is to elucidate, at the molecular level, how an extra copy of normal genes in human trisomy 21 produces the DS phenotype. The ultimate goal is to identify those genes and relate the increased amounts of their gene products to the genesis of specific defects that tipify the syndrome. To accomplish this, two genes residing at the 21q22 segment, Cu/Zn-superoxide dismutase and liver type phosphofructokinase, will be cloned, characterized and introduced as part of recombinant plasmid vectors into normal cells as well as into mouse embryos. Transformed cell clones and transgenic mice expressing elevated levels of the two human genes will be isolated and examined for consequent physiological changes. This strategy will enable us to study the dosage effect of each gene individually apart from effects produced in DS by other chromosome 21 encoded genes, and should lead to an understanding of how an imbalanced expression of these genes contributes directly or indirectly to the DS phenotype. The information gained in this study should permit definition of the biochemical pathways affected in the syndrome, and allow the development of therapies to ameliorate or prevent at least some of the symptoms of DS and related disorders.